1. Field of the Invention
The present invention is directed to the field of molecular genetics of cancer. Specifically, the present invention relates to human lymphomas in which a translocation between chromosomes 2 and 5 (referred to in the art as "t(2;5)") has occurred. On a molecular level, the DNA rearrangement in t(2;5) results in the fusion of the known NPM gene with a novel gene named ALK (Anaplastic Lymphoma Kinase) that encodes a protein tyrosine kinase (PTK).
2. Related Art
Chromosomal abnormalities are frequently associated with malignant diseases. In a number of instances, specific chromosomal translocations have been characterized, which generate fusion genes encoding proteins with oncogenic properties (Sawyers et al., Cell 64:337-350 (1991)). Perhaps the best example of genetic characterization of a malignant disease is provided by the analysis of the chromosomal abnormalities unique to different subsets of non-Hodgkin's lymphoma (NHL). The NHL subset commonly referred to as large cell lymphoma (which comprises .about.25% and 40% of NHL in children and adults, respectively) has historically been the most ill-defined because of its marked cytological, immunological and clinical heterogeneity.
Approximately one-third of large cell lymphomas (10% of all NHL) contain the t(2;5)(p23;q35), usually as the only cytogenetic abnormality (R. Rimokh et al., Br. J. Haematol. 71:31-36 (1989); D. Mason et al., Br. J. Haematol. 74:161-168 (1990); H. Stein and F. Dallenbach, in Neoplastic Hematopathology, D. M. Knowles, ed., Williams & Wilkins, Baltimore (1992), pp. 675-714), suggesting that rearrangement of cellular proto-oncogenes on these chromosomes contributes to lymphomagenesis.
The majority of t(2;5)-positive lymphomas (70-75%) express T-lymphoid markers, although usually in the aberrant, incomplete fashion characteristic of T-cell malignancies (e.g., preservation of CD2 and CD4 with infrequent expression of CD3) (M. E. Kadin, J. Clin. Oncol. 12:884-887 (1994); J. T. Sandlund et al., Blood 84:2467-2471 (1994)). Less commonly, these neoplasms bear B-cell markers (.about.15%) or have a null phenotype with neither B- nor T-antigen expression (10%). Lymphomas with the t(2;5) typically involve lymph nodes, skin, lung, soft tissue, bone and the gastrointestinal tract, and arise predominantly from activated T lymphocytes (Y. Kaneko et al., Blood 73:806-813 (1989); M. M. Le Beau et al., Leukemia 3:866-870 (1989); R. Rimokh et al., Br. J. Haematol. 71:31-36 (1989); D. Y. Mason et al., Br. J. Haematol. 74:161-168 (1990); M. A. Bitter Am. J. Surg. Pathol. 14:305-316 (1990); M. E. Kadin, J. Clin. Oncol. 9:533-536 (1991); J. P. Greer et al., J. Clin. Oncol. 9:539-547 (1991); V. Vecchi et al., Med. Pediatr. Oncol. 21:402-410 (1993)). The malignant cells express IL-2 receptors and CD30 (Ki-1) antigen, a receptor for a newly described member of the tumor necrosis factor ligand family (H. Durkop et al., Cell 68:421-427 (1992); C. A. Smith et al., Cell 73:1349-1360 (1993)). By the updated Kiel lymphoma classification, most tumors with the t(2;5) are classified as anaplastic large cell non-Hodgkin's lymphomas (A. G. Stansfeld et al., Lancet 1:292-293 (1988)). These tumors typically behave as aggressive, high-grade NHL with most patients having advanced stage disease at presentation. From 30% to 40% of patients eventually succumb to their disease despite aggressive therapeutic intervention.